Perinatal hypoxia-ischemia (HI) remains a serious problem in the care of newborns. Interruption in the supply of oxygenated blood to the brain may result in neuronal injury, encephalopathy and possibly death. Neonatal encephalopathy (NE) occurs in 3-9 of every 1000 term infants. Hypothermia decreases or inhibits many of the cellular events that lead to neuronal damage after reperfusion, and offers the advantage of an early and relatively uncomplicated intervention in a potentially devastating disease process. The safety and efficacy of short-term systemic hypothermia during HI has been established in adult and neonatal populations undergoing cardiac and neurosurgical procedures. The safety and efficacy of longer-term systemic hypothermia (1-5 days) has been substantiated in adult head trauma patients and in 17 newborns with junctional tachyarrhythmias, but not in this population of HI newborns. Before a full-scale clinical trial of this intervention is designed and conducted, we need to validate the uniformity of the intervention protocol and define outcome measures. In this pilot study we will enroll 72 successive newborns within 6 hours of an HI event, and randomly assign them to hypothermia (33 C) or normothermia (37.5 C) for 48 hours after HI insult. This study will test a degree of systemic hypothermia which may have the greatest neuroprotective effect with few adverse effects based on studies in human infants and our preliminary feasibility study of 5 term newborns. We will address measures of efficacy and safety, refine the treatment protocol and the target population for the full-scale clinical trial. We will show that systemic hypothermia can be safely and uniformly begun at outlying hospitals and during transport of newborns to a tertiary care center. The use of hypothermia in this disease process may be groundbreaking and profoundly change the way asphyxiated newborns are treated even in the most rural areas. Questions regarding measures of safety and efficacy of hypothermia, novel methods for identification of neonates in first few hours after the insult, and outcome predictions for these newborns need to be better defined prior to a definitive clinical trial.